Mutated stem cells trigger pituitary tumours in children

A type of pituitary tumour known
as craniopharyngioma appears to form via a different mechanism to that thought
to occur in more common tumours, according to a paper in the journal Cell Stem Cell.

The novel findings, generated
by a team led by the UCL Institute of Child Health (ICH), will be further
explored to better understand how cell signalling triggers the growth of such
tumours – the third most common brain tumour in children - and whether new
treatments could be devised to block these signals.

The ICH study, funded by the
Wellcome Trust, used mouse models to investigate cells in the pituitary gland
which are thought to act as stem cells, in that they give rise to all the
different cell types in the gland. Researchers used a genetic approach to
follow these cells and the 'daughters' they produced, establishing that they did
indeed generate new hormone-producing cells across all the different
specialised types.

However, when the original cells acquired
a genetic mutation often found in the childhood tumour adamantinomatous
craniopharyngioma, instead of dividing uncontrollably to generate the tumour,
they sent signals to induce changes in nearby cells, causing the latter to divide and give rise to the tumour.
The team now needs to determine how widespread this alternative tumour-forming
model is across the range of endocrine tumours and cancers.

Understanding what signals these cells are releasing in the pituitary gland could help us to find new treatments that specifically block the signals and prevent or slow down the growth of the tumour.

Dr Juan Pedro Martinez-Barbera, UCL Institute of Child Health

The pituitary
gland, a small endocrine (hormone-producing) organ, controls a multitude of
functions in the body. Termed the ‘Master Gland’, it directs other organs and endocrine glands by
producing hormones that regulate blood sugar, blood pressure, metabolism and
growth in children, and also control the sex hormones and thereby reproduction
and sexual function.

Pituitary tumours arise in around
one in 1,000 people. Most of these tumours are adenomas, which usually respond
well to surgery and/or radiotherapy.

Craniopharyngioma, though much rarer, is the
third most common brain tumour in children. Craniopharyngioma can behave
aggressively and tends to infiltrate nearby structures such as the brain and
optic tracts, leading to severe and life-threatening side effects, including
blindness, severe obesity, sleep disorders and type 2 diabetes mellitus, which can
result in a poor quality of life for many patients.

The molecular mechanisms
underlying most pituitary tumours have remained unknown up to now; these tumours
rarely contain cells carrying mutations in the most commonly found oncogenes
and tumour suppressor genes critical in other human tumours and cancers. The
ICH study reveals a new possible mechanism which could explain how pituitary
tumours form.

Professor Mehul Dattani,
Paediatric Endocrinologist at Great Ormond Street Hospital and co-author of the
study, says: “Craniopharyngiomas are currently treated by removing most of
the tumour surgically, and then giving the patient radiotherapy. These tumours
often recur and there is no specific treatment targeting the mutated stem cells.”

Dr Juan Pedro Martinez-Barbera, who
led the research team at the UCL Institute of Child Health, adds: “The next
stage of our research will be to better understand the mechanisms that take
place after the cells acquire the mutation which leads to them to produce the
tumour-promoting signals. Understanding what signals these cells are releasing
in the pituitary gland could help us to find new treatments that specifically
block the signals and prevent or slow down the growth of the tumour.

“Advanced cancer can be very
powerful, with cells having developed multiple ways to evade the patient’s
immune system and generate new cancer cells that are resistant to treatments. At
the initial stages of tumour formation, tumour cells are easier to target and
eliminate. Early diagnosis of cancer and new treatments targeting tumour cells would
help to boost survival rates as well as reducing the damaging effects of both
cancer and the intensive treatments required to eradicate it.”